1. Field of the Invention
The present invention is directed to compounds that are tri-aryl substituted ethanes. In particular, this invention is directed to ethanes substituted with i) a phenyl, ii) a thiazole, and iii) a pyridyl moiety which are phosphodiesterase-4 inhibitors.
2. Related Background
Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3xe2x80x2, 5xe2x80x2-cyclic monophosphate, xe2x80x9ccAMPxe2x80x9d or xe2x80x9ccyclic AMPxe2x80x9d) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Thus, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.
Phosphodiesterases (xe2x80x9cPDExe2x80x9d) are a family of enzymes that metabolize 3xe2x80x2, 5xe2x80x2 cyclic nucleotides to 5xe2x80x2 nucleoside monophosphates, thereby terminating cAMP second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 (xe2x80x9cPDE4xe2x80x9d, also known as xe2x80x9cPDE-IVxe2x80x9d), which is a high affinity, cAMP specific, type IV PDE, has generated interest as potential targets for the development of novel anti-asthmatic and anti-inflammatory compounds. PDE4 is known to exist as at lease four isoenzymes, each of which is encoded by a distinct gene. Each of the four known PDE4 gene products is believed to play varying roles in allergic and/or inflammatory responses. Thus, it is believed that inhibition of PDE4, particularly the specific PDE4 isoforms that produce detrimental responses, can beneficially affect allergy and inflammation symptoms. It would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
Inhibition of PDE4 activity is believed effective for the treatment of osteoporosis by reducing bone loss. For example, Ken-ici Miyamoto et al., Biochem. Pharmacology, 54:613-617(1997) describes the effect of a PDE4 on bone loss. Therefore, it would be desirable to provide novel compounds and compositions that inhibit PDE4 activity.
A major concern with the use of PDE4 inhibitors is the side effect of emesis which has been observed for several candidate compounds as described in C. Burnouf et al., (xe2x80x9cBurnoufxe2x80x9d), Ann. Rep. In Med. Chem., 33:91-109(1998). B. Hughes et al., Br. J. Pharmacol., 118: 1183-1191(1996); M. J. Perry et al., Cell Biochem. Biophys., 29:113-132(1998); S. B.Christensen et al., J. Med. Chem., 41:821-835(1998); and Burnouf describe the wide variation of the severity of the undesirable side effects exhibited by various compounds. As described in M. D. Houslay et al., Adv. In Pharmacol., 44:225-342(1998) and D. Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research of therapeutic PDE4 inhibitors.
U.S. Pat. Nos. 5,622,977, 5,710,160, 5,710,170, 5,798,373, 5,849,770, and International Patent Publication No. WO 99/50262 describe tri-substituted aryl derivative PDE IV inhibitors, including tri-aryl ethane derivatives.
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition. International Patent Publication WO9422852 describes quinolines as PDE4 inhibitors.
U.S. Pat. Nos. 5,491,147, 5,608,070, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,859,034, 5,866,593, 5,891,896, and International Patent Publication WO 95/35283 describe PDE4 inhibitors that are tri-substituted aryl or heteroaryl phenyl derivatives. U.S. Pat. No. 5,580,888 describes PDE4 inhibitors that are styryl derivatives. U.S. Pat. No. 5,550,137 describes PDE4 inhibitors that are phenylaminocarbonyl derivatives. U.S. Pat. No. 5,340,827 describes PDE4 inhibitors that are phenylcarboxamide compounds. U.S. Pat. No. 5,780,478 describes PDE4 inhibitors that are tetra-substituted phenyl derivatives. International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. U.S. Pat. No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
However, there remains a need for novel compounds and compositions that therapeutically inhibit PDE4 with minimal side effects.
The present invention is directed to novel tri-aryl substituted ethanes. In particular, this invention is directed to ethanes substituted with i) a phenyl, ii) a thiazole, and iii) a pyridyl moiety which are phosphodiesterase-4 inhibitors. This invention also provides a pharmaceutical composition which includes an effective amount of the novel tri-aryl substituted ethanes and a pharmaceutically acceptable carrier. This invention further provides a method of treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn""s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth, cancerous invasion of normal tissues, osteoporosis, and bone loss by the administration of an effective amount of the novel ethanes substituted with i) a phenyl, ii) a thiazole, and iii) a pyridyl moiety which are phosphodiesterase-4 inhibitors.
A compound of this invention is represented by Formula (I): 
or a pharmaceutically acceptable salt thereof, wherein
R1 is C1-6alkyl or C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, C2-6alknenyl, C2-6alkynyl, C3-6cycloalkyl, or xe2x80x94C1-6alkylC3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is C1-4alkyl, C3-6cycloalkyl, heteroaryl, or phenyl, any of which optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen;
n is 0 or 1; and
when R3 and R4 are connected to each other through X, then R3 and R4 are each C1alkyl, and X is C0-4alkyl.
According to one aspect, a compound of this invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl or C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is C1-4alkyl, C3-6cycloalkyl, heteroaryl, or phenyl, any of which optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen;
n is 0 or 1; and
when R3 and R4 are connected to each other through X, then R3 and R4 are each C1alkyl, and X is C0-4alkyl.
According to one embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R3 is C1-4alkyl, C3-6cycloalkyl, heteroaryl, or phenyl, any of which optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen;
n is 0 or 1; and
when R3 and R4 are connected to each other through X, then R3 and R4 are each C1alkyl, and X is C0-4alkyl.
According to another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R3 is C1-4alkyl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to yet another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R3 is C3-6cycloalkyl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to an embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R3 is heteroaryl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to an embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R3 is phenyl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to still another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R3 and R4 are connected to each other through X;
R3 and R4 are each C1alkyl;
X is C0-4alkyl;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is C1-4alkyl, C3-6cycloalkyl, heteroaryl, or phenyl, any of which optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen;
n is 0 or 1; and
when R3 and R4 are connected to each other through X, then R3 and R4 are each C1alkyl, and X is C0-4alkyl.
According to another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is C1-4alkyl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to yet another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is C3-6cycloalkyl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to an embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is heteroaryl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to an embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 is phenyl, optionally substituted independently with 1-4 independent halogen or C1-6alkyl;
R4 is H or C1-4alkyl, said alkyl optionally substituted with 1-4 independent halogen;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
According to still another embodiment of this aspect,
R1 is C1-6alkyl, optionally substituted with 1-4 independent halogen;
R2 is C3-6cycloalkyl, optionally substituted with 1-4 independent halogen;
R3 and R4 are connected to each other through X;
R3 and R4 are each C1alkyl;
X is C0-4alkyl;
RP is H, halogen, nitrile, or a C1-6alkyl group, said alkyl optionally substituted with 1-4 independent halogen; and
n is 0 or 1.
As used herein, xe2x80x9calkylxe2x80x9d as well as other groups having the prefix xe2x80x9calkxe2x80x9d such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. xe2x80x9cAlkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d and other like terms include carbon chains containing at least one unsaturated Cxe2x80x94C bond.
The term xe2x80x9ccycloalkylxe2x80x9d means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene and the like. Similarly, xe2x80x9ccycloalkenylxe2x80x9d means carbocycles containing no heteroatoms and at least one non-aromatic Cxe2x80x94C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.
The term xe2x80x9carylxe2x80x9d means an aromatic substituent that is a single ring or multiple rings fused together. When formed of multiple rings, at least one of the constituent rings is aromatic. The preferred aryl substituents are phenyl and napthyl groups.
The term xe2x80x9ccycloalkyloxyxe2x80x9d unless specifically stated otherwise includes a cycloalkyl group connected by a short C1-C2alkyl length to the oxy connecting atom.
The term xe2x80x9cC0-C6alkylxe2x80x9d includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. An alkyl with no carbon atoms is a hydrogen atom substituent.
The term xe2x80x9cheteroxe2x80x9d unless specifically stated otherwise includes one or more N, O, or S atoms. Heterocycloalkyl and heteroaryl are ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms. The hetero atoms replace ring carbon atoms. Thus, for example, a heterocycloC5alkyl is a five member ring containing from 5 to no carbon atoms. The term xe2x80x9cheteroarylxe2x80x9d means an aryl group that has at least one heteroatom in the ring. The preferred heteroaryl groups are 5 and 6 member rings having 1-4 heteroatoms independently selected from N, O, or S.
The term xe2x80x9caminexe2x80x9d unless specifically stated otherwise includes primary, secondary and tertiary amines.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine and iodine atoms.
The term xe2x80x9coptionally substitutedxe2x80x9d is intended to include both substituted and unsubstituted. Thus, for example, optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring. Further, optionally substituted multiple moieties such as, for example, alkylaryl are intended to mean that the aryl and the aryl groups are optionally substituted. If only one of the multiple moieties is optionally substituted then it will be specifically recited such as xe2x80x9can alkylaryl, the aryl optionally substituted with halogen or hydroxyl.xe2x80x9d
Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers.
Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. The above Formula (I) is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
The pharmaceutical compositions of the present invention comprise a compound represented by Formula (I) (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, and iii) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
Dosage levels from about 0.01 mg/kg to about 140 mg/kg of body weight per day are useful in the treatment of conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn""s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth and cancerous invasion of normal tissues which are responsive to PDE4 inhibition, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day. Further, it is understood that the PDE4 inhibiting compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 1 mg to about 500 mg of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
In practice, the compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula (I), or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula (I). The compounds of Formula (I), or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared, by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula (I) of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula (I), or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
The compounds and pharmaceutical compositions of this invention have been found to exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn""s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease, hypersecretion of gastric acid, bacterial, fungal or viral induced sepsis or septic shock, inflammation and cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth and cancerous invasion of normal tissuesxe2x80x94maladies that are amenable to amelioration through inhibition of the PDE4 isoenzyme and the resulting elevated cCAMP levelsxe2x80x94by the administration of an effective amount of the compounds of this invention. The term xe2x80x9cmammalsxe2x80x9d includes humans, as well as other animals such as, for example, dogs, cats, horses, pigs, and cattle. Accordingly, it is understood that the treatment of mammals other than humans is the treatment of clinical correlating afflictions to those above recited examples that are human afflictions.
Further, as described above, the compound of this invention can be utilized in combination with other therapeutic compounds. In particular, the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, or iii) M2/M3 antagonists.
Whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE4-selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-xcex1 and LTB4. Upon stimulation with LPS, activated monocytes express and secrete TNF-xcex1 up to 8 hours and plasma levels remain stable for 24 hours. Published studies have shown that inhibition of TNF-xcex1 by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity occurs at the transcriptional level. LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE4-selective inhibitors. As there is little LTB4 produced during a 24 hour LPS stimulation of whole blood, an additional LPS stimulation followed by fMLP challenge of human whole blood is necessary for LTB4 synthesis by activated neutrophils. Thus, by using the same blood sample, it is possible to evaluate the potency of a compound on two surrogate markers of PDE4 activity in the whole blood by the following procedure.
Fresh blood was collected in heparinized tubes by venipuncture from healthy human volunteers (male and female). These subjects had no apparent inflammatory conditions and had not taken any NSAIDs for at least 4 days prior to blood collection. 500 xcexcL aliquots of blood were pre-incubated with either 2 xcexcL of vehicle (DMSO) or 2 xcexcL of test compound at varying concentrations for 15 minutes at 37xc2x0 C. This was followed by the addition of either 10 xcexcL vehicle (PBS) as blanks or 10 xcexcL LPS (1 xcexcg/m-L final concentration, #L-2630 (Sigma Chemical Co., St. Louis, Mo.) from E. coli, serotype 0111:B4; diluted in 0.1% w/v BSA (in PBS)). After 24 hours of incubation at 37xc2x0 C., another 10 xcexcL of PBS (blank) or 10 xcexcL of LPS (1 xcexcg/mL final concentration) was added to blood and incubated for 30 minutes at 37xc2x0 C. The blood was then challenged with either 10 xcexcL of PBS (blank) or 10 xcexcL of fMLP (1 xcexcM final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37xc2x0 C. The blood samples were centrifuged at 1500xc3x97g for 10 minutes at 4xc2x0 C. to obtain plasma. A 50 xcexcL aliquot of plasma was mixed with 200 xcexcL methanol for protein precipitation and centrifuged as above. The supernatant was assayed for LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann Arbor, Mich.) according to the manufacturer""s procedure. TNF-xcex1 was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, N.J.) according to manufacturer""s procedure. The IC50 values of Examples 1-36 generally ranged from 0.01 xcexcM to 20 xcexcM.
Compounds of the invention have been tested for effects on an IgE-mediated allergic pulmonary inflammation induced by inhalation of antigen by sensitized guinea pigs. Guinea pigs were initially sensitized to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in combinations with aluminum hydroxide and pertussis vaccine. Booster doses of antigen were given two and four weeks later. At six weeks, animals were challenged with aerosolized ovalbumin while under cover of an intraperitoneally administered anti-histamine agent (mepyramine). After a further 48 h, bronchial alveolar lavages (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted. The lungs were also removed for histological examination for inflammatory damage. Administration of compounds of the Examples (0.001-10 mg/kg i.p. or p.o.), up to three times during the 48 h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples.
Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IV cAMP-specific phosphodiesterases were screened in a 96-well plate format as follows:
In a 96 well-plate at 30xc2x0 C. was added the test compound (dissolved in 2 xcexcL DMSO), 188 mL of substrate buffer containing [2,8-3H] adenosine 3xe2x80x2, 5xe2x80x2-cyclic phosphate (cAMP, 100 nM to 50 xcexcM), 10 mM MgCl2, 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 mL of human recombinant PDE4 (the amount was controlled so that xcx9c10% product was formed in 10 min.). The reaction was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, N.J.). The product AMP generated was quantified on a Wallac Microbeta(copyright) 96-well plate counter (EGandG Wallac Co., Gaithersburg, Md.). The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted. Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multiple binding sites equation from a ten point titration.
The IC50 values of Examples 1-36 were determined with 100 nM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression system. The IC50 values of Examples 1-36 generally ranged from 0.05 nm to 200 nm.
The examples that follow are intended as an illustration of certain preferred embodiments of the invention and no limitation of the invention is implied.
Unless specifically stated otherwise, the experimental procedures were performed under the following conditions. All operations were carried out at room or ambient temperaturexe2x80x94that is, at a temperature in the range of 18-25xc2x0 C. Evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60xc2x0 C. The course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only. Melting points are uncorrected and xe2x80x98dxe2x80x99 indicates decomposition. The melting points given are those obtained for the materials prepared as described. Polymorphism may result in isolation of materials with different melting points in some preparations. The structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. Yields are given for illustration only. When given, NMR data is in the form of delta (xcex4) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent. Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc. In addition, xe2x80x9cArxe2x80x9d signifies an aromatic signal. Chemical symbols have their usual meanings; the following abbreviations have also been used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
The compounds of Formula (I) of the present invention can be prepared according to the synthetic routes outlined in Schemes 1 to 3 below and by following the methods described therein. It is obvious to one skilled in the art that resolution of compounds bearing stereogenic centers, such as VII, XIII to XVI for example, or compounds of Formula I and Ia, can be accomplished by one of several methods, including HPLC with a chiral column, or formation and crystallization of a salt prepared by reaction of the compound with a chiral acid or base. The substituents are the same as in Formula (I) except where defined otherwise. It is apparent that RP is readily incorporated into the compounds of this invention by starting with the appropriately substituted alkyl pyridylacetate reactant.
Scheme 1
The thiazole tertiary alcohols of Formula I may be prepared in a multi-step sequence from the requisite dialkoxyaldehyde III and an appropriately substituted thiazole II as presented in Scheme 1 below. Addition of a metalated thiazole, prepared by regioselective metalation of thiazole II with a base such as n-butyllithium in a suitable solvent such as ether or THF, to III provides secondary alcohol IV. Conversion of IV into the corresponding secondary chloride or bromide V is accomplished by reaction with an appropriate halogenating reagent, such as thionyl chloride or thionyl bromide, and an organic base, such as pyridine, diisopropylethylamine or triethylamine, in an organic solvent such as dichloromethane or toluene. Alkylation of the anion derived from deprotonation of an alkyl pyridylacetate with an appropriate base, such as lithium, sodium or potassium bis(trimethylsilyl)amide, with the halide V in an appropriate organic solvent such as THF and/or HMPA (hexamethylphosphoramide), provides the ester VI. Ester VI is decarboxylated by one of several methods to give the pyridine VII.
In one method, heating VI in the presence of aqueous hydroxide, such as sodium hydroxide, in a mixture of protic and aprotic organic solvents, such as methanol or ethanol and THF, followed by acidification of the intermediate carboxylic acid with mineral acid, such a hydrochloric acid, provides VII. Alternatively, heating the carboxylic acid in an organic solvent such as dimethylsulfoxide provides VII.
Removal of the alcohol protecting group, for example by treating with an organic acid such as trifluoroacetic acid in an organic solvent such a dichloromethane (if P=2-(trimethylsilyl)ethoxymethoxy), affords the pyridines of Formula Ia of the present invention. Reaction of Ia with an oxidizing agent, such as m-CPBA (meta-chloroperoxybenzoic acid) or MMPP (monoperoxyphthalic acid, magnesium salt) provides the N-oxides of Formula I of the present invention. Alternatively, oxidation of VII as described above for Ia, followed by deprotection affords the N-oxides of Formula I of the present invention. 
Scheme 2
Alternatively, compounds of Formula I can be prepared using the route described in Scheme 2 below. Alkylation of the anion derived from deprotonation of an alkyl pyridylacetate N-oxide with an appropriate base, such as lithium, sodium or potassium bis(trimethylsilyl)amide, with the secondary halide V in an appropriate organic solvent such as THF and/or HMPA, provides the ester VIII. Decarboxylation and deprotection as described in Scheme 1 provides the N-oxides of Formula I of the present invention. 
Scheme 3
The thiazole tertiary alcohols of Formula I may also be prepared in a multi-step sequence from the requisite dialkoxyaldehyde III and an appropriately substituted thiazole IX as presented in Scheme 3 below via the intermediacy of the aldehyde XIV. Addition of a metalated thiazole, prepared by regioselective metalation of thiazole IX in a suitable solvent such as ether or THF, to III provides secondary alcohol X. Conversion of X into the corresponding secondary chloride or bromide XI is accomplished by reaction with an appropriate halogenating reagent, such as thionyl chloride or thionyl bromide, and an organic base, such as pyridine, diisopropylethylamine or triethylamine, in an organic solvent such as dichloromethane or toluene. Alkylation of the anion derived from deprotonation of an alkyl pyridylacetate with an appropriate base, such as lithium, sodium or potassium bis(trimethylsilyl)amide, with the halide XI in an appropriate organic solvent such as THF and/or HSPA, provides the ester XII. Ester XII is decarboxylated as described in Scheme 1 above to give XIII. Removal of the aldehyde protecting group by reaction of XIII with an acid, such as hydrochloric acid or p-toluenesulfonic acid, provides aldehyde XIV. Treatment of aldehyde XIV with a nucleophilic reagent, such as an organolithium, organocerium or Grignard reagent, in an organic solvent, such as ether or THF, provides the secondary alcohol XV. Oxidation of XV with an oxidizing agent, such as manganese dioxide or by Swern oxidation, affords ketone XVI. Further reaction of ketone XVI with a second nucleophilic reagent, such as an organolithium, organocerium or Grignard reagent, in an organic solvent such as ether or THF, provides the pyridines of Formula Ia of the present invention. Reaction of Ia with an oxidizing agent, such as m-CPBA or MMPP provides the N-oxides of Formula I of the present invention. 